The overall goal of Project 1 is to define the genetic barriers to successful allogeneic hematopoietic cell transplantation (HCT). HCT from unrelated donors can cure blood disorders. Complete and precise donor HLA matching is associated with superior transplant outcome. However, risks of graft-versus-hostdisease and mortality are still increased compared to sibling donor transplantation. Furthermore, 20- 40% ofpatients who start a search fail to identify suitably matched donors. Criteria for selecting optimal mismatched donors are ill-defined. Recently, new information on,KIR receptors demonstrates the importance of HLA-KIR interactions in alloresponses after HCT. The long-term objectives of Project 1 are to improve theavailability, safety and efficacy of HCT by optimizing donor genetic selection. The specific aims are to: 1) define the extent to which availability of unrelated HCT can be increased through the use of HLA mismatcheddonors by identifying permissible mismatches; 2) identify new MHC-resident genes associated with transplant outcome, and 3) determine if HLA-KIR interactions modify risk of post-transplant complications. Successin achieving these goals will broaden the applicability of unrelated HCT to the treatment of blood disorders.